A balanced level of vitamin D has long been recognized as essential to health. Vitamin D appears to increase the efficiency of the intestines to absorb calcium and also mobilizes calcium from bone tissue when required. A deficiency in vitamin D leads to rickets, a debilitating bone disease while excessive levels of vitamin D are toxic. Although use of vitamin D as a food supplement has significantly reduced the incidence of disease caused by vitamin D deficiency, vitamin D is not a naturally occurring nutrient and is present only in low levels in few foods. Oral delivery of vitamin D has been described as ineffective, unnatural and potentially dangerous since toxic amounts of vitamin D may be inadvertently ingested. All recorded cases of vitamin D toxicity have resulted from oral delivery of toxic amounts.
The skin is a major site of cholesterol production and humans naturally acquire vitamin D through the action of ultraviolet light on the skin. 7-Dehydrocholesterol, which is unstable to ultraviolet light, is along the metabolic pathway toward cholesterol. Ultraviolet light breaks open the B-ring of the 7-dehydrocholesterol molecule to generate previtamin D.sub.3, which spontaneously isomerizes over hours and days into vitamin D.sub.3. An unknown proportion of the vitamin D.sub.3 from the skin is absorbed into the circulation. Unabsorbed previtamin D.sub.3 and vitamin D.sub.3 are made non-functional in the skin by oxidation or by the action of ultraviolet light. Vitamin D.sub.3 is not soluble in water, and in the circulation, there is a protein that specifically binds to and carries vitamin D and its metabolites. The advantage of ultraviolet exposure is that it has no vitamin D toxicity associated with it. The disadvantage is that the availability of ultraviolet light is unreliable, too much of it causes cancer, and at northern latitudes there is not always enough ultraviolet light intensity outdoors to generate previtamin D.sub.3.
To become effective, vitamin D must go through two metabolic steps. Vitamin D is readily changed by the liver to 25-hydroxyvitamin D, which is measured in serum to reflect vitamin D nutritional status. 25-hydroxyvitamin D has little, if any, per se biological activity. The kidney metabolizes 25-hydroxyvitamin D into the active hormone, 1, 25-dihydroxyvitamin D, which affects calcium transport across cell membranes. Production of 1, 25-dihydroxyvitamin D is carefully regulated by the body, according to its mineral requirements.
Very few foods naturally contain vitamin D. Mellanby, J Physiol (London) volume 52:1iii (1919), instituted the idea that an artificial supplement, cod-liver oil, contained an agent that prevented rickets; the agent became known as vitamin D. Most of the vitamin D in our food is supplementary, synthetic material, which is either in the form of vitamin D.sub.3, the form naturally produced in animals, or it can be vitamin D.sub.2, which is derived from a plant steroid. The term, vitamin D, refers to either the D.sub.2 or D.sub.3 forms. The advantages of adding vitamin D to the diet are well known. The disadvantages are that orally acquired vitamin D can be toxic (reference, Vieth, Bone and Mineral, volume 11: 267-272; 1990) and that people with impaired fat absorption will not absorb it well from the gut. Furthermore, it is known that vitamin D behaves differently in the circulation depending on whether it enters via the gut or the skin. Haddad JG, et al J Clin Invest volume 91:2552; 1993 showed that oral vitamin D.sub.2 enters the circulation mixed with dietary fats in chylomicrons and it becomes partially activated into 25-hydroxyvitamin D.sub.2 relatively quickly. In contrast, these authors showed that the vitamin D.sub.3 generated from exposure of experimental subjects to ultraviolet lamps will circulate unchanged for a prolonged time when combined with its specific transport protein, i.e. vitamin D-binding protein (DBP), and not with chylomicrons. Fraser, in a review of how the body handles vitamin D, Lancet, April 30, 1983:969 concluded, "The oral route as a means of supplying vitamin D is ineffective, unnatural, and potentially dangerous. Yet, to achieve adequate exposure to the sun of whole populations such as those in large cities may well prove impractical. Human ingenuity might therefore have to devise another way of providing vitamin D--one which takes into account the natural physiology of its formation and processing in the human body."
U.S. Pat. No. 2,060,228 issued to Lorenz AJ, describes a soap having incorporated therein an antirachitic factor having beneficial dermatological properties.
Vitamin D together with vitamin A have been added to ointments used for minor skin irritations, diaper rash, chafing, skin dryness, etc., and they are particles. One alternative is, typically, sold as "A & D Ointment".
Vitamin D is fat soluble and is generally administered in such ointments in an oil based vehicle such as petroleum gel, in a vehicle such as propylene glycol. The percutaneous delivery of vitamin D using such ointments is unreliable and likely only locally significant for the following reasons. Vitamin D is very sensitive to sunlight since it is decomposed readily by ultraviolet light. Such ointments are indicated for minor local skin ailments and cannot be a reliable source of the body's vitamin D requirement. The oily vehicles render the ointments unsuitable for general application to the body and staining of clothing would result if so used. Indeed the manufacturers of A&D ointments do not claim any benefit from the presence of the vitamins. The amount of vitamin D delivered using such ointments is likely insignificant due to rapid decomposition in sunlight, and restriction to local intermittent use.
In recognition of the risk of vitamin D deficiency thorough use of sunblocking lotions, vitamin D or its precursors have been added to such lotions. In U.S. Pat. No. 3,981,996 issued to Leigh Sep. 21, 1976 a topical skin cream as a drug delivery system was described. The cream comprised a continuous hydrophobic medium in which were disposed inert water soluble particles. One embodiment in Leigh included vitamins A and D absorbed on such particles within a conventional sunscreen preparation Leigh described a sun screening preparation having mixtures of vitamin A and D in an amount from 50,000 to 5,000,000 I.U. per gram but otherwise does not provide details of the benefits of such delivery or reasons for the recommended concentrations. Presumably the primary focus of Leigh is a drug delivery system wherein vitamin D is only one of the example given. In light of current knowledge of vitamin D toxicity, the concentrations specified by Leigh are potentially toxic. Indeed to provide the phenomenally high vitamin concentration described in Leigh, the use of such a particle delivery system is necessary.
Vitamin D.sub.3 has been administered to the shaved skin of rats at a dose of 50 .mu.g in 10 .mu.L 95% ethanol (Holick M. F., Uskokovic M., Henley J. W., MacLaughlin F., Holick S. A., Potts J. T. The photoproduction of 1,25-dihydroxyvitamin D.sub.3 in skin--an approach to the therapy of vitamin-D-resistant syndromes. N Engl J Med 1980; 303:349-354). The vitamin D.sub.3 -treated rats served as a negative control group for which no response was detected; in contrast, application of 1,25(OH).sub.2 D.sub.3, or 1,25-dihydroxylated-7-dehydrocholesterol increased intestinal calcium transport and serum calcium in their experiment. A subsequent patent by Holick, U.S. Pat. No. 4,310,511 issued Jan. 12, 1982, indicates that dermal uptake is inefficient and that there could be an "uncontrolled increase in absorption of vitamin D, with concomitant loss of concentration control, and the appearance of side effects such as vitamin D toxicity" (column 3, line 18).
In U.S. Pat. No. 4,310,511 a sunscreen composition is described including a precursor to vitamin D. The precursor or previtamin D is absorbed by the skin and cutaneously synthesized into vitamin D by the natural thermal process of the epidermis as described above. Holick recognizes the risk of vitamin D toxicity and addresses the issue by utilizing only non-hydroxylated steroid precursors in the composition. Holick submits that vitamin D toxicity is due to circulating levels of hydroxylated forms of vitamin D (at positions 1; 1,25; 1,24,25; or 1,23,26). By supplying non-hydroxylated steroids only, Holick states that the natural regulatory mechanisms of the body prevent overproduction of vitamin D from its precursors and resultant toxicity. It is now recognized that the hydroxylations producing potent forms of vitamin D are driven by the vitamin D supply through mass action relationships, Vieth, The Mechanisms Of Vitamin D Toxicity, Bone and Mineral, 11 (1990) 267-272).
It is therefore important to determine the total quantity of vitamin D entering the body and not merely the hydroxylated forms as proposed by Holick. Vitamin D intoxication should be characterized by measurement of the total concentration of all vitamin D metabolites and the concentrations of 1,25 (OH).sub.2 D and DBP. This regulation of total vitamin D intake is required since it is now recognized that a probable mechanism for vitamin D toxicity is that high 25 (OH)D concentration will cause both the excessive synthesis of 1,25 (OH).sub.2 D and together with vitamin D and its other metabolites cause displacement of the hormone from DBP thereby increasing the amount of free 1,25(OH).sub.2 D that is accessible to target cells. Regulation of 1,25(OH).sub.2 D, and other selected hydroxylated provitamins as proposed by Holick is not sufficient to prevent toxicity in light of current knowledge.
The amount of vitamin D precursor proposed by Holick is so large that if all of it were synthesized into vitamin D by the epidermis, toxicity would result. Holick's method of replenishing the vitamin D supply has not been proven to be reproducible and likely involves a large degree of error. Since vitamin D is supplied indirectly through selected non-hydroxylated precursors, Holick's method of preventing toxicity involves several unknowns such as the rate and efficiency of previtamin D to vitamin D synthesis, and the effect of DBP displacement.
Notwithstanding the above teachings of the prior there remains a need for a suitable and efficacious method of administering nutritional or therapeutic amounts of vitamin D to humans.